Previous studies identified the PD-1 expression ratio between CD8 + effector T cells and Treg in the TME as a predictive marker for immune checkpoint blockade efficacy. Here, we confirmed that PD-1 expression on eTreg is significantly higher than on CD8 + T cells in cervical cancer, explaining the limited response to anti-PD-1 therapy. High TNFR2 expression impairs anti-PD-1 efficacy and exacerbates this PD-1 imbalance. RNA sequencing and untargeted metabolomics showed TNFR2 regulates the Warburg effect: TNFR2 downregulation reduces glucose uptake, lactate secretion, and ATP production, while glycolysis inhibition reverses TNFR2-mediated tumorigenesis in nude mouse xenografts. Lactate was identified as a key mediator of the PD-1 imbalance. Mechanistically, TNFR2 regulates tumor glycolysis via the PI3K/Akt/mTOR/c-Myc pathway, with c-Myc driving glycolytic gene expression. Inhibiting PI3K, mTOR, or c-Myc reverses TNFR2-induced glycolytic enzyme upregulation, while Akt activation restores their expression after TNFR2 downregulation. Our study identifies a novel TNFR2-PI3K/Akt/mTOR/c-Myc-glycolysis-lactate-PD-1 imbalance axis, proposing TNFR2 inhibitors enhance anti-PD-1 efficacy by reversing this imbalance. Combining TNFR2 blockade with anti-PD-1 therapy may improve cervical cancer treatment outcomes.

Lung cancer is one of the most common and deadly forms of cancer worldwide, with >80% of cases being non‑small cell lung cancer. Its recurrence and drug resistance have been major challenges in clinical treatment, posing a serious threat to the lives of patients. The present study found that high xeroderma pigmentosum group C (XPC) expression markedly reduced the proliferation capacity and stem cell characteristics of the lung cancer cell lines A549‑XPC and H460‑XPC. In addition, XPC overexpression led to a decreased in the proportion of cells in the G2/M phase proportion, suggesting alterations in the cell cycle process. MTS assays showed that XPC overexpressing cells demonstrated markedly higher sensitivity to chemotherapy drugs compared with control cells. Furthermore, the clonogenic and anchorage‑independent spheroid formation capacities of the cells were markedly inhibited with high XPC expression and the phosphorylation levels of the JAK/STAT pathway and the expression levels of stemness‑associated markers were markedly altered. In vivo studies validated the effect of high XPC expression on tumorigenicity using a subcutaneous tumor model, with tumor volumes of 134.04±46.77 mm³ and 324.64±85.31 mm³ and weights of 164.24±76.16 mg and 434.70±115.72 mg for subcutaneously injected A549‑XPC and A549‑CTR cells, respectively. High expression of XPC in the A549 cells significantly affected tumor volume (P<0.05) and weight (P<0.01) in vivo. The present findings suggested that high XPC expression is associated with reduced proliferation, migration and stem cell‑like properties in lung cancer cells, enhances their sensitivity to chemotherapy drugs and suppresses tumor growth in vivo. These observations supported further investigation of XPC as a potential therapeutic target and prognostic marker for lung cancer, offering new strategies to improve treatment outcomes and prolong patient survival.

The autophagy-lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy-lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques, hyperphosphorylated tau tangles, and significant neuronal loss. Recent studies have implicated YKL-40, a glycoprotein commonly associated with inflammation and neural apoptosis, in the pathogenesis of AD. Methods We conducted extensive searches across major scientific databases, including PubMed, Web of Science, and Embase. We selected peer-reviewed articles, review articles, and clinical studies focusing on YKL-40 in AD. Results This review comprehensively analyses the multifaceted role of YKL-40 in AD, covering its cellular localization, biomarker associations, and pathological mechanisms. We also summarize the mechanistic pathways by which YKL-40 contributes to disease progression, highlighting its role in neuroinflammation, neural apoptosis, and disruption of the circadian regulation of immune responses. Moreover, the development of drugs that target YKL-40, such as humanized anti-YKL-40 antibodies and small molecules, offers promising strategies for blocking AD progression. Conclusion This review highlights the potential of YKL-40 as a novel drug target and its implications for enhancing diagnostic precision and treatment strategies in combating Alzheimer’s disease.

Switch/sucrose non-fermentable (SWI/SNF) related matrix associated actin-dependent regulator of chromatin sub-family A member 4-deficient undifferentiated carcinoma (SMARCA4-DUC) of the small intestine is a rare and highly aggressive subtype of gastrointestinal malignancy. The present study reported the case of SMARCA4-DUC in a patient who presented with intestinal intussusception and multi-organ metastasis to the lungs, liver, spleen and skin, which led to rapid progression and death in 43 days. The present case highlighted the unique histological and molecular features of SMARCA4-DUC, characterized by the absence of SMARCA4 expression and undifferentiated cellular morphology. The present case report aimed to describe the clinical presentation, imaging findings, pathological features and treatment course, to further the current understanding of SMARCA4-associated malignancies and improve the recognition of SMARCA4-DUC among clinicians and pathologists. Next-generation sequencing of the primary small intestinal tumor identified pathogenic mutations in PTEN, TP53, ataxia telangiectasia mutated, ephrin type-A receptor 5 and EGFR p.F997L, suggesting a DNA-repair-deficient genomic background and providing potential targets for future precision therapy. Further research is warranted to determine the molecular mechanisms underlying SMARCA4-DUC, for the development of targeted therapeutic strategies and to improve the understanding of the aggressiveness of SMARCA4-DUC.

YKL-40 is a glycoprotein that has been extensively studied due to its elevated expression in numerous solid tumors, and its expression is altered in melanoma, where its levels in tumor tissues are notably lower compared with those in normal skin tissues. Patients with melanoma exhibiting high YKL-40 expression have improved survival rates, suggesting a potential tumor-suppressive function of YKL-40 in melanoma. The present investigation into the ectopic expression of YKL-40 in human (A375) and murine (B16F10) melanoma cell lines demonstrated a consequential decrease in cell proliferation, migration and invasion. Furthermore, YKL-40 overexpression was associated with suppressed tumor growth in a subcutaneous melanoma mouse model and diminished tumor cell metastasis in a pulmonary metastasis model. RNA-sequencing analysis revealed that YKL-40 overexpression led to the upregulation of immune cell infiltration-related signaling pathways, including cytokine receptor interactions, natural killer cell-mediated cytotoxicity, and T and B lymphocyte receptor signaling. These findings highlight the potential of YKL-40 as a regulator of tumor-immune interactions in melanoma, highlighting its prospective utility in immunotherapy-based treatment strategies for melanoma.

Lymph node metastasis (LNM) in cervical cancer is a critical determinant of the disease progression and prognosis. Elucidating its molecular mechanisms and identifying specific biomarkers are crucial for optimizing treatment. DIA-based quantitative proteomic sequencing was conducted on 49 cervical cancer patients. We screened differentially expressed proteins and performed functional enrichment, pathway scoring, time-series analysis, protein interaction studies, and integrated proteomic and TCGA transcriptomic data to identify biomarkers. 56 genes showed consistent expression trends, with 2 upregulated (SERPINB5, FABP5) and 54 downregulated (including ZNF512). Novel findings include activation of unsaturated fatty acid/steroid biosynthesis and inhibition of cell junction pathways during progression. Lymphovascular space invasion (LVSI) precedes LNM, but a subset of LNM cases lacks LVSI and exhibits a unique cholesterol metabolism activation. SERPINB5, FABP5, and ZNF512 were validated as potential prognostic and LNM-predictive biomarkers. DIA proteomics characterized cervical cancer lymph node metastasis, revealing molecular changes and potential biomarkers and offering new insights into its biological mechanisms.

The forkhead box O1 (FOXO1), the first discovered member of the FoxO family, is a critical transcription factor predominantly found in insulin-secreting and insulin-sensitive tissues. In the pancreas of adults, FoxO1 expression is restricted to islet β cells. We determined that in human islet microarray datasets, FoxO1 expression is higher than other FoxO transcription factors. Our analyses of three human islet datasets revealed that FoxO1 expression tends to shows a negative correlation with type 2 diabetes and no correlation with body mass index (BMI) between individuals with low levels of HbA1C (or ND, non-diabetic) and high levels of HbA1C (or T2D, type 2 diabetes). However, FoxO1 function is multifaceted and mainly regulated by post-translational modifications including phosphorylation and deacetylation that involved in pancreatic β cell function and insulin sensitivity. This study summarized the molecular mechanisms underlying the role of FoxO1 activity in pancreatic β-cell dysfunction and insulin resistance in T2D. In addition, we discussed the therapeutic potential of FoxO1 inhibitors in diabetes treatment.

Glioma is one of the most common primary malignant tumors of the central nervous system, with a poor prognosis and easy recurrence after surgery. Exploring potential biomarkers is highly important for early detection, diagnosis, and disease evaluation. Abnormal expression of integrins is closely related to tumor metastasis, promoting both tumor metastasis and angiogenesis through intracellular signaling pathways. In this study, the expression levels of ITGA and ITGB superfamily genes in glioma was obtained from the GEPIA and CGGA databases, and the differences in their expression between tumor and normal tissues were compared. Combined with the known tumor marker IDH, correlations were analyzed to explore the relationships between the expression levels of ITGA and ITGB superfamily genes and patient prognosis. These results suggest that ITGA3, ITGA5, ITGB5, and ITGB8 are highly expressed in glioblastoma and could be used as potential biomarkers. In low-grade gliomas, the expressions of ITGA6, ITGB1, ITGB2, ITGB5, and ITGB8 were significantly increased, which could be used as biomarkers. In early gliomas, ITGA3, ITGA5, ITGB1, ITGB2, ITGB5, and ITGB8 are highly expressed in patients with IDH wild-type glioma,and the prognosis is good. Therefore, these genes can be used as early biomarkers. These findings indicate that the expression of ITGA and ITGB superfamily genes, as biomarkers, has important clinical significance in the grading, diagnosis and prognostic analysis of glioma.

N 6-methyladenosine (m6A) is the most abundant mRNA modification in mammals and it plays a vital role in various biological processes. However, the roles of m6A on cervical cancer tumorigenesis, especially macrophages infiltrated in the tumor microenvironment of cervical cancer, are still unclear. We analyzed the abnormal m6A methylation in cervical cancer, using CaSki and THP-1 cell lines, that might influence macrophage polarization and/or function in the tumor microenvironment. In addition, C57BL/6J and BALB/c nude mice were used for validation in vivo. In this study, m6A methylated RNA immunoprecipitation sequencing analysis revealed the m6A profiles in cervical cancer. Then, we discovered that the high expression of METTL14 (methyltransferase 14, N6-adenosine-methyltransferase subunit) in cervical cancer tissues can promote the proportion of programmed cell death protein 1 (PD-1)-positive tumor-associated macrophages, which have an obstacle to devour tumor cells. Functionally, changes of METTL14 in cervical cancer inhibit the recognition and phagocytosis of macrophages to tumor cells. Mechanistically, the abnormality of METTL14 could target the glycolysis of tumors in vivo and vitro. Moreover, lactate acid produced by tumor glycolysis has an important role in the PD-1 expression of tumor-associated macrophages as a proinflammatory and immunosuppressive mediator. In this study, we revealed the effect of glycolysis regulated by METTL14 on the expression of PD-1 and phagocytosis of macrophages, which showed that METTL14 was a potential therapeutic target for treating advanced human cancers.

Immunotherapy is a potent tool used in cancer treatment, but the occurrence of immune-related adverse events induced by immune checkpoint inhibitors (ICIs) cannot be overlooked. This is particularly true for rare but potentially fatal cardiovascular complications, such as myocarditis; heart muscle inflammation may lead to heart dysfunction and arrhythmia. The present case is a 68-year-old female breast cancer patient who developed palpitations and elevated cardiac enzyme levels after 1 day of ICI therapy, and the patient was eventually diagnosed with immune myocarditis. After receiving hormonal shock therapy, Ctn I, CK, CK-MB and other cardiac enzyme-related markers improved significantly, and electrocardiogram test returned to normal, and the patient recovered during hospitalization without any major adverse cardiac events. Furthermore, the present study reviewed the mechanism of immune myocarditis induced by ICI therapy, with the aim of providing a clinical foundation for the prevention and diagnosis of cardiovascular adverse events in ICI therapy.

Background Cervical cancer has the second-highest mortality rate among malignant tumors of the female reproductive system. Immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) blockade are promising therapeutic agents, but their efficacy when combined with neoadjuvant chemotherapy (NACT) has not been fully tested, and how they alter the tumor microenvironment has not been comprehensively elucidated.Methods In this study, we conducted single-cell RNA sequencing using 46,950 cells from nine human cervical cancer tissues representing sequential different stages of NACT and PD-1 blockade combination therapy. We delineated the trajectory of cervical epithelial cells and identified the crucial factors involved in combination therapy. Cell-cell communication analysis was performed between tumor and immune cells. In addition, THP-1-derived and primary monocyte-derived macrophages were cocultured with cervical cancer cells and phagocytosis was detected by flow cytometry. The antitumor activity of blocking CD74 was validated in vivo using a CD74 humanized subcutaneous tumor model.Results Pathway enrichment analysis indicated that NACT activated cytokine and complement-related immune responses. Cell-cell communication analysis revealed that after NACT therapy, interaction strength between T cells and cancer cells decreased, but intensified between macrophages and cancer cells. We verified that macrophages were necessary for the PD-1 blockade to exert antitumor effects in vitro. Additionally, CD74-positive macrophages frequently interacted with the most immunoreactive epithelial subgroup 3 (Epi3) cancer subgroup during combination NACT. We found that CD74 upregulation limited phagocytosis and stimulated M2 polarization, whereas CD74 blockade enhanced macrophage phagocytosis, decreasing cervical cancer cell viability in vitro and in vivo.Conclusions Our study reveals the dynamic cell-cell interaction network in the cervical cancer microenvironment influenced by combining NACT and PD-1 blockade. Furthermore, blocking tumor-associated macrophage-derived CD74 could augment neoadjuvant therapeutic efficacy.

The occurrence of unexplained recurrent spontaneous abortion (URSA) is closely related to immune system disorders, however, the underlying mechanisms remain unclear. The purpose of this study was to investigate the expression of GRIM-19 in URSA and the possible pathogenesis of URSA according to macrophage polarization. Here, we showed that GRIM-19 was downregulated in the uterine decidual macrophages of patients with URSA and that GRIM-19 downregulation was accompanied by increased M1 macrophage polarization. Furthermore, the expression levels of glycolytic enzymes were substantially enhanced in the uterine decidual macrophages of URSA patients, and glycolysis in THP-1-derived macrophages was further enhanced by the downregulation of GRIM-19. Additionally, the increase of M1 macrophages resulting from the loss of GRIM-19 was significantly reversed in cells treated with 2-deoxy-D-glucose (2-DG, an inhibitor of glycolysis). To provide more direct evidence, GRIM-19 deficiency was shown to promote macrophage polarization to the M1 phenotype in GRIM-19+/- mouse uteri. Overall, our study provides evidence that GRIM-19 deficiency may play a role in regulating macrophage polarization in URSA, and that glycolysis may participate in this process.

As a promising therapeutic approach, immunotherapy is being extensively investigated in cervical cancer. Although immunotherapy has been validated to improve progression-free survival and overall survival in clinical trials, the overall response rate for cervical cancer remains inadequate, necessitating further improvement. Interleukin (IL)-37, an emerging immunomodulator, exhibits antitumour potentials by inhibiting tumour progression and regulating tumour-associated macrophage recognition. We found a significant downregulation of IL-37 expression in cervical cancer, correlated with a poor prognosis. Moreover, the upregulation of IL-37 expression exhibited a suppressive effect on various tumorigenic processes, suppressing the proliferation, invasion, migration, apoptosis and angiogenesis of tumour cells. We also found that the upregulation of IL-37 suppressed cluster of differentiation 47 (CD47) expression in tumour cells via suppression of the signal transducer and activator of transcription 3 (STAT3) expression and phosphorylation, thereby enhancing macrophage recognition and phagocytosis to tumour cells, ultimately reducing immune evasion. Overall, our study highlighted the crucial role of IL-37 in antitumour efficacy and downregulating the expression of CD47 in tumour cells to reduce immune evasion, suggesting the potential of IL-37 as a prognostic biomarker in cervical cancer and offering innovative therapeutic strategies to improve cancer treatment outcomes.

Diffuse cystic lung diseases (DCLDs) are a group of heterogeneous lung diseases that are characterized by inflated spaces or cysts within the lung parenchyma. They also exhibit similar imaging characteristics and clinical manifestations compared with those of cystic lesions, such as pulmonary cavities, emphysema, bronchiectasis and honeycomb lung. The most common DCLDs encountered in the clinic include lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, Langerhans cell histiocytosis and lymphocytic interstitial pneumonia. In particular, accurate diagnosis of DCLDs in terms of the different lesions found is important, because their clinical courses, prognoses and treatment strategies vary widely. However, because DCLDs usually have overlapping clinical presentations, diagnosis typically requires a combination of clinical considerations that take into account characteristics of the cyst, its distribution, organ of origin and background parenchymal findings. The present report documents the case of a 73-year-old man diagnosed with desquamative interstitial pneumonia (DIP). The patient was admitted to the hospital due to chest tightness, shortness of breath and intermittent fever. The patient had been a smoker for >60 years and had stopped smoking for 6 months before being admitted. A transbronchial lung biopsy, bronchoscopy and alveolar lavage cytopathogen culture were performed to confirm the diagnosis of desquamative interstitial pneumonia (DIP). The patient was treated with hormonal therapy and advised to abstain from smoking. The diagnosis of DIP in comparison with other DCLDs was summarized for the purpose of providing a clinical basis for the accurate clinical diagnosis of DIP and the development of evidence-based practice guidelines.

Following ischemic stroke, Ccl5 mRNA expression increased, while miR-324-5p expression decreased in the peri-infract cortex of middle cerebral artery occlusion (MCAO) mice. However, the roles of CCL5 and miR-324-5p in stroke remain unclear. Here, we show that inhibiting CCL5 using antibodies or miR-324-5p not only reduced infarct area and preserved neurological function in MCAO mice but also attenuated astrocyte and microglia activation, protected dendritic structures, and maintained spine density. In an astrocyte-neuron co-culture system after oxygen-glucose deprivation (OGD), knockdown astrocytic CCL5 expression by antibody or miR-324-5p decreased neuronal apoptosis and preserved dendritic architecture. Importantly, the suppression of CCL5 enhanced the activation of the ERK/CREB pathway both in vivo and in vitro. Consistent with these findings, the application of Maraviroc, a CCR5 antagonist, reduced infarct size, decreased neuronal apoptosis, and upregulated the ERK/CREB pathway in neurons treated with OGD. In conclusion, targeting the CCL5 pathway via miR-324-5p represents a promising therapeutic strategy for alleviating ischemic stroke damage through modulation of neuronal CCR5/ERK/CREB pathway.

Globally, non‑small cell lung cancer (NSCLC) is a significant threat to human health, and constitutes >80% of lung cancer cases. Cisplatin (CDDP), a commonly used drug in clinical treatment, has been the focus of research aiming to mitigate its potent toxicity through encapsulation within liposomes. However, challenges, such as a reduced drug loading efficiency and nonspecific release, have emerged as obstacles. The present study aimed to improve the encapsulation efficiency of CDDP within liposomes by pre‑preparation of CDDP and modifying the liposome surface through the incorporation of peanut agglutinin (PNA) as a ligand [CDDP‑loaded PNA‑modified liposomes (CDDP‑PNA‑Lip)]. This strategy was designed to enhance the delivery of CDDP to tumour tissues, thereby reducing associated side effects. The effect of CDDP‑PNA‑Lip on the proliferation and migration of NSCLC cell lines with high MUC1 expression was elucidated through in vitro studies. Additionally, the capacity of PNA modification to augment the targeted anti‑tumour efficacy of liposomes was assessed through xenograft tumour experiments. The results indicated that in an in vitro uptake assay Rhodamine B (RhB)‑loaded PNA‑modified liposomes were taken up by cells with ~50% higher efficiency compared with free RhB. In addition, CDDP‑PNA‑Lip resulted in a 2.65‑fold enhancement of tumour suppression in vivo compared with free CDDP. These findings suggested that the encapsulation of CDDP within ligand‑modified liposomes may significantly improve its tumour‑targeting capabilities, providing valuable insights for clinical drug development.

Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN has been implicated in the development of multiple tumours. Herein, we determined the effect of APLN on the biological behaviour and underlying mechanisms of cervical cancer. The expression and survival curves of APLN were determined using Gene Expression Profiling Interactive Analysis. The cellular functions of APLN were detected using CCK-8, clone formation, EdU, Transwell assays, flow cytometry, and seahorse metabolic analysis. The underlying mechanisms were elucidated using gene set enrichment analysis and Western blotting. APLN was upregulated in the samples of patients with cervical cancer and is associated with poor prognosis. APLN knockdown decreased the proliferation, migration, and glycolysis of cervical cancer cells. The opposite results were observed when APLN was overexpressed. Mechanistically, we determined that APLN was critical for activating the PI3K/AKT/mTOR pathway via APLNR. APLN receptor inhibitor ML221 reversed the effect of APLN overexpression on cervical cancer cells. Treatment with LY294002, the PI3K inhibitor, drastically reversed the oncological behaviour of APLN-overexpressing C-33A cells. APLN promoted the proliferation, migration, and glycolysis of cervical cancer cells via the PI3K/AKT/mTOR pathway.

Lung cancer is the most common cancer in the world due to its high incidence and recurrence. Genetic instability is one of the main factors leading to its occurrence, development and poor prognosis. Decreased xeroderma pigmentosum group C (XPC) expression notably enhances the stem cell properties of lung cancer cells and increases their proliferation and migration. Additionally, patients with lung cancer and low XPC expression had a poor prognosis. The purpose of the present study was to analyze the effect of XPC and IFN-gamma on the clinical prognosis of patients with non-small cell lung cancer (NSCLC). Lung adenocarcinoma specimens were collected from a total of 140 patients with NSCLC. Additionally, from these 140 patients, 48 paracarcinoma tissue specimens were also collected, which were later used to construct tissue microarrays. The expression of XPC and IFN-gamma in cancer tissues and in paraneoplastic tissues was detected using immunohistochemistry. The prognosis and overall survival of patients were determined through telephone follow-up. The results showed a positive correlation between expression of XPC and IFN-gamma in NSCLC. Additionally, high expression of both markers was associated with a favorable prognosis in patients with NSCLC. The aforementioned findings suggest that the expression of XPC and IFN-gamma has prognostic value in clinical practice and is expected to become a marker for clinical application.